title: A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels.
abstract: OBJECTIVE
  Minor variation in serum thyroid hormone (TH) levels can have important effects on various clinical endpoints. Although 45-65% of the inter-individual variation in serum TH levels is due to genetic factors, the causative genes are not well established. We therefore studied the effects of genetic variation in 68 TH pathway genes on serum TSH and free thyroxine (FT(4)) levels.
  
  
  METHODS
  Sixty-eight genes (1512 polymorphisms) were studied in relation to serum TSH and FT(4) levels in 1121 Caucasian subjects. Promising hits (P<0.01) were studied in three independent Caucasian populations (2656 subjects) for confirmation. A meta-analysis of all four studies was performed.
  
  
  RESULTS
  For TSH, eight PDE8B polymorphisms (P=4×10(-17)) remained significant in the meta-analysis. For FT(4), two DIO1 (P=8×10(-12)) and one FOXE1 (P=0.0003) polymorphisms remained significant in the meta-analysis. Suggestive associations were detected for one FOXE1 (P=0.0028) and three THRB (P=0.0045) polymorphisms with TSH, and one SLC16A10 polymorphism (P=0.0110) with FT(4), but failed to reach the significant multiple-testing corrected P value (P<0.0022 and P<0.0033 respectively).
  
  
  CONCLUSIONS
  Using a large-scale association analysis, we replicated previously reported associations with genetic variation in PDE8B, THRB, and DIO1. We demonstrate effects of genetic variation in FOXE1 on serum FT(4) levels, and borderline significant effects on serum TSH levels. A suggestive association of genetic variation in SLC16A10 with serum FT(4) levels was found. These data provide insight into the molecular basis of inter-individual variation in TH serum levels.
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Medici
authors.forename: Wendy M
authors.initials: WM
authors.lastname: van der Deure
authors.forename: Michael
authors.initials: M
authors.lastname: Verbiest
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.forename: Pia S
authors.initials: PS
authors.lastname: Hansen
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Ad R M M
authors.initials: AR
authors.lastname: Hermus
authors.forename: Monique M
authors.initials: MM
authors.lastname: Breteler
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Laszlo
authors.initials: L
authors.lastname: Hegedüs
authors.forename: Kirsten Ohm
authors.initials: KO
authors.lastname: Kyvik
authors.forename: Martin
authors.initials: M
authors.lastname: den Heijer
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: Robin P
authors.initials: RP
authors.lastname: Peeters
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000097:blood / Q000235:genetics*; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011159:Population Surveillance / Q000379:methods; D011446:Prospective Studies; D015398:Signal Transduction / Q000502:physiology*; D013963:Thyroid Hormones / Q000097:blood / Q000235:genetics; D013974:Thyroxine / Q000097:blood* / Q000235:genetics*
chemical_list: C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D013963:Thyroid Hormones; D013974:Thyroxine